Hepatocellular Carcinoma (HCC) is the third leading cause of cancer deaths worldwide. The main PET tracer currently used in oncology applications, 2-[18F]-fluoro-2-deoxy-D-glucose (FDG), has been shown to be ineffective for imaging HCC since many HCCs do not show differential FDG uptake comparing to the surrounding hepatic tissues. Identification of aggressive liver lesions with rapid growth (proliferation) with PET imaging also proves to be difficult since several thymidine analogs (all substrates of thymidine kinase (TK)) developed for proliferation imaging did not work well in the liver due mainly to glucuronidation, which leads to a high liver background uptake. We propose to investigate a newly developed tracer, 1-(2'-deoxy- 2'-[18F]-fluoro-?-D-arabinofuranosyl)cytosine ([18F]-FAC, a substrate more specific for deoxycytidine kinase (dCK) than for TK), which displays a lower liver background uptake. A modifier, tetrahydrouridine (THU, an inhibitor of cytidine deaminase (CDA)), will be added to suppress enzymatic activity of hepatic CDA and maintain FAC activity in the liver. We plan to establish this [18F]-FAC and THU combination for PET imaging of proliferation in HCC based on encouraging preliminary pre-clinical results and clinical biodistribution studies. Our central hypothesis is that FAC uptak is correlated with dCK-dependent proliferation in HCC; and [18F]-FAC-PET (THU) can be used to identify aggressive HCC and to predict response to dCK-dependent treatment. We will test this hypothesis via the following Specific Aims. Aim 1: To confirm the mechanism of [18F]-FAC uptake in HCC with a clinically relevant woodchuck model of HCC; Aim 2: To validate [18F]-FAC-PET (THU) uptake in patients with HCC; Aim 3: To explore the utility of [18F]-FAC-PET (THU) as a companion imaging biomarker for predicting the response to novel dCK-dependent treatment such as the new therapeutic combination of THU-decitabine.